DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Invention I, drawn to a double-stranded RNA molecule, in the reply filed on 01/21/2026 is acknowledged.
Claims 35-36 and 49-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/21/2026.
Claims Status
Claims 2, 4-12, 18-19, 25, 29, 31-40, 42-45, 48-54, 56-59, 61, 63 is/are cancelled and claims 67-71 is/are newly added. Claims 1, 3, 13-17, 20-24, 26-28, 30, 41, 46-47, 55, 60, 62, 64-71 is/are currently pending with claims 35-36, 49-50 withdrawn. Claims 1, 3, 13-17, 20-24, 26-28, 30, 41, 46-47, 55, 60, 62, 64-71 is/are under examination.
Claim Interpretation
Claims 1, 26-27, 41, and 64-65 recite sequences indicated as being SEQ ID NOs:1-5; however, the sequences recited in the claims comprise uridines at the same nucleotide positions as thymidines in the corresponding sequences in the sequence listing. As SEQ ID NOs:1-5 in the sequence listing are indicated to be RNA molecules, and uridines are generally used in place of thymidine in RNA molecules, the sequences recited in the claims as SEQ ID NOs:1-5 and the sequences of SEQ ID NOs:1-5 in the sequence listing are considered to be the same or equivalent.
Claims 28 and 47 recite an intended use of the claimed product of a pharmaceutical composition comprising the dsRNA molecule of claim 1 (claim 28) or the branched RNA compound of claim 41 (claim 47). According to MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. The intended use recited in claims 28 and 47 does not appear to impart any structure to either claimed product. Therefore for the purpose of this action, claims 28 and 47 are directed to a pharmaceutical composition comprising the dsRNA molecule of claim 1 (claim 28) or the branched RNA compound of claim 41 (claim 47), and a pharmaceutically acceptable carrier.
Claim Objections
Claim 22 is objected to because of the following informalities:
Claim 22 recites that “the sense strand comprises at least 65% 2’-O-methyl nucleotide modifications.” The plain English reading of this phrase would encompass sense strand nucleotides comprising 65% of a 2’-O-methyl modification. As this is not a common concept in the art, but 65% of the nucleotides of a sequence comprising a modification is a common concept in the art, the latter is considered the most reasonable interpretation. For clarity, the examiner suggests claim 22 read as follows: “The dsRNA molecule of claim 3, wherein 65% of the nucleotides of the sense strand comprise 2’-O-methyl nucleotide modifications.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
112(b):
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13, 60, 62 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 recites “at least one modified internucleotide linkage of Formula I” (line 2). Formula I, as depicted in claim 13, comprises two nucleotides, with variable elements covalently bound to the 2’ and 3’ carbons of the sugar rings of both nucleotides (X and Z), and three variable elements covalently bound to the internucleotide phosphorus atom (W, Y, Z). While element X is described as being halo, hydroxy, or C1-6 alkoxy (line 7) (and thus, a modified element), element X is not part of the internucleotide linkage. It is therefore unclear whether the dsRNA molecule comprising at least one modified internucleotide linkage of Formula I requires a modification of X and a modification of at least one of W, Y, or Z, or if the element X is, for the purposes of the claims, considered part of a “modified internucleotide linkage”, and a dsRNA molecule of claim 13 must comprise a modification of at least one of W, X, Y, or Z. Claims 14-17 depend on claim 13 but do not clarify this indefiniteness, and therefore are also rejected for indefiniteness.
The term “about” in claim 60 and 62 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “about” is used in the claims to modify the concentrations of different chemical compounds. The specification does not provide a definition for the term “about”. There is no definition of the term “about” that is commonly accepted in the art, and as such, the term “about” must be defined by the applicant. Without a definition, the term “about” implies a range of acceptable error which is potentially limitless. Without a proper definition of this term, the metes and bounds of the acceptable error for a value modified by the term “about” cannot be determined.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 13-17, 20-24, 28, 41, 47, 60, 62, 66-71 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khvorova (WO2021173984A2).
Regarding claim 1, Khvorova teaches a double-stranded RNA (dsRNA) molecule (claim 4) comprising a sense strand and an antisense strand (claim 5), wherein the antisense strand comprises a sequence comprising no more than 3 mismatches with SEQ ID NO:3 and comprising 15-25 nucleotides in length (claims 6-7, 9). Instant SEQ ID NO:1 comprises one mismatch relative to the complement of SEQ ID NO:3, and instant SEQ ID NO:2 is substantially identical to (comprising one mismatch relative to) SEQ ID NO:3 (see alignment below) (claim 49, paragraph [030], the sense strand is complementary to the antisense strand).
SEQ ID NO:3 and instant SEQ ID NO:1:
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SEQ ID NO:3 and instant SEQ ID NO:2:
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Regarding claim 2, Khvorova teaches that the dsRNA comprises at least one modified nucleotide (claim 26).
Regarding claim 13, Khvorova teaches that the dsRNA molecule comprises at least one modified nucleotide or internucleotide linkage of Formula (I):
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Wherein B is a base pairing moiety;
W is selected from the group consisting of O, OCH2, OCH, CH2, and CH;
X is selected from the group consisting of halo, hydroxy, and C1-6 alkoxy;
Y is selected from the group consisting of O-, OH, OR, NH-, NH2, S-, and SH;
Z is selected from the group consisting of O and CH2;
And
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indicates an optional double bond (claim 32).
Regarding claim 14, Khvorova teaches that in an embodiment, W is OCH2 and Z is O (paragraph [0309]).
Regarding claim 15, Khvorova teaches that the antisense strand comprises at least one modified internucleotide linkage (claim 43).
Regarding claims 16-17, Khvorova teaches that the 2-6 3’-terminal nucleotides of the antisense strand are connected by phosphorothioate linkages (claim 45).
Regarding claim 20, Khvorova teaches that “the antisense strand comprises at least 70% 2’-O-methyl modifications” (claim 46).
Regarding claim 21, Khvorova teaches that the antisense strand is 15-25 nucleotides long (claim 9), and thus an antisense strand comprising at least 70% 2’-O-methyl modifications must comprise at least 10 2’-O-methyl modifications (70% of 15 nucleotides is 10.5 nucleotides).
Regarding claim 22, Khvorova teaches that “the sense strand comprises at least 70% 2’-O-methyl modifications” (claim 46).
Regarding claim 23, Khvorova teaches that the sense strand is 15-25 nucleotides long (claim 9), and thus a sense strand comprising at least 70% 2’-O-methyl modifications must comprise at least 10 2’-O-methyl modifications (70% of 15 nucleotides is 10.5 nucleotides).
Regarding claim 24, Khvorova teaches that the antisense strand further comprises a 5’ phosphate, a 5’-alkyl phosphonate, a 5’-alkylene phosphonate, or a 5’ alkenyl phosphonate (claim 43).
Regarding claim 28, Khvorova teaches a pharmaceutical composition for inhibiting expression of a PRNP gene in an organism, comprising the dsRNA molecule and a pharmaceutically acceptable carrier (claim 68).
Regarding claim 41, Khvorova teaches a branched RNA compound comprising two or more dsRNA molecules (claims 85, 88), wherein each of the dsRNA molecules comprises an antisense strand and a sense strand (claim 91), and wherein the antisense strand comprises a sequence comprising no more than 3 mismatches with SEQ ID NO:3 and comprising 15-25 nucleotides in length (claims 91-93, 95). Instant SEQ ID NO:1 comprises one mismatch relative to the complement of SEQ ID NO:3, and instant SEQ ID NO:2 is substantially identical to (comprising one mismatch relative to) SEQ ID NO:3 (see alignment above) (claim 131, paragraph [030], the sense strand is complementary to the antisense strand).
Regarding claim 47, Khvorova teaches a pharmaceutical composition for inhibiting expression of a PRNP gene in an organism, comprising the branched RNA compound and a pharmaceutically acceptable carrier (claim 173).
Regarding claims 60 and 62, the term “about”, as used in the instant claims, indicates an unlimited margin of error. As such, instant claims 60 and 62 encompass any concentration of branched RNA comprised in the pharmaceutical composition. Khvorova teaches a pharmaceutical composition for inhibiting expression of a PRNP gene in an organism, comprising the branched RNA compound (of unspecified concentration, thus any concentration) and a pharmaceutically acceptable carrier (claim 173). Likewise, instant claims 60 and 62 encompass K(PO4)2, NaCl, Na(PO4)2, and MgPO4 concentrations of 0 mg/mL. Khvorova does not teach pharmaceutical compositions comprising K(PO4)2, NaCl, Na(PO4)2, or MgPO4, thus encompassing certain embodiments of claims 60 and 62.
Regarding claim 66, Khvorova teaches that the branched RNA compound comprises at least one modified nucleotide or internucleotide linkage of Formula (I):
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Wherein B is a base pairing moiety;
W is selected from the group consisting of O, OCH2, OCH, CH2, and CH;
X is selected from the group consisting of halo, hydroxy, and C1-6 alkoxy;
Y is selected from the group consisting of O-, OH, OR, NH-, NH2, S-, and SH;
Z is selected from the group consisting of O and CH2;
And
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indicates an optional double bond (claim 118).
Regarding claims 67-68, Khvorova teaches that the dsRNA further comprises at least one phosphorothioate internucleotide linkage (claim 29).
Regarding claim 69, Khvorova teaches that the dsRNA molecule comprises a 2’-O-methyl modified nucleotide, a 2’-deoxy-2’-fluoro modified nucleotide, a 2’-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoroamidate, a non-natural base comprising nucleotide, or a mixture thereof (claim 27).
Regarding claim 70, Khvorova teaches that the antisense strand comprises a 5’ vinyl phosphonate (claim 44).
Regarding claim 71, Khvorova teaches that the branched RNA compound comprises a modified internucleotide linkage according to Formula I, wherein W is OCH2, and Z is O (paragraphs [0307], [0309]; claim 118), resulting in instant Formula VI:
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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 13-17, 20-24, 26-28, 41, 47, 60, 62, 64-71 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khvorova (WO2021173984A2).
Regarding claim 1, Khvorova teaches a double-stranded RNA (dsRNA) molecule (claim 4) comprising a sense strand and an antisense strand (claim 5), wherein the antisense strand comprises a sequence comprising no more than 3 mismatches with SEQ ID NO:3 and comprising 15-25 nucleotides in length (claims 6-7, 9). Instant SEQ ID NO:1 comprises one mismatch relative to the complement of SEQ ID NO:3, and instant SEQ ID NO:2 is substantially identical to (comprising one mismatch relative to) SEQ ID NO:3 (see alignment below) (claim 49, paragraph [030], the sense strand is complementary to the antisense strand).
SEQ ID NO:3 and instant SEQ ID NO:1:
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SEQ ID NO:3 and instant SEQ ID NO:2:
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Regarding claim 2, Khvorova teaches that the dsRNA comprises at least one modified nucleotide (claim 26).
Regarding claim 13, Khvorova teaches that the dsRNA molecule comprises at least one modified nucleotide or internucleotide linkage of Formula (I):
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Wherein B is a base pairing moiety;
W is selected from the group consisting of O, OCH2, OCH, CH2, and CH;
X is selected from the group consisting of halo, hydroxy, and C1-6 alkoxy;
Y is selected from the group consisting of O-, OH, OR, NH-, NH2, S-, and SH;
Z is selected from the group consisting of O and CH2;
And
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indicates an optional double bond (claim 32).
Regarding claim 14, Khvorova teaches that in an embodiment, W is OCH2 and Z is O (paragraph [0309]).
Regarding claim 15, Khvorova teaches that the antisense strand comprises at least one modified internucleotide linkage (claim 43).
Regarding claims 16-17, Khvorova teaches that the 2-6 3’-terminal nucleotides of the antisense strand are connected by phosphorothioate linkages (claim 45).
Regarding claim 20, Khvorova teaches that “the antisense strand comprises at least 70% 2’-O-methyl modifications” (claim 46).
Regarding claim 21, Khvorova teaches that the antisense strand is 15-25 nucleotides long (claim 9), and thus an antisense strand comprising at least 70% 2’-O-methyl modifications must comprise at least 10 2’-O-methyl modifications (70% of 15 nucleotides is 10.5 nucleotides).
Regarding claim 22, Khvorova teaches that “the sense strand comprises at least 70% 2’-O-methyl modifications” (claim 46).
Regarding claim 23, Khvorova teaches that the sense strand is 15-25 nucleotides long (claim 9), and thus a sense strand comprising at least 70% 2’-O-methyl modifications must comprise at least 10 2’-O-methyl modifications (70% of 15 nucleotides is 10.5 nucleotides).
Regarding claim 24, Khvorova teaches that the antisense strand further comprises a 5’ phosphate, a 5’-alkyl phosphonate, a 5’-alkylene phosphonate, or a 5’ alkenyl phosphonate (claim 43).
Regarding claims 26-27, Khvorova teaches that the antisense strand comprises alternating 2’-methoxy-ribonucleotides (2’-O-methyl) and 2’-fluoro-ribonucleotides (claim 45, wherein the second nucleotide from the 5’ end is 2’-fluoro modified), phosphorothioate linkages between the three 5’- and 3’-terminal nucleotides (paragraph [0495]), and modified internucleotide linkages of formula (I) between the three 3’-terminal nucleotides (a phosphorothioate linkage, according to Formula (I), has “S” selected as the identity of “Y”) (paragraph [0495], claim 45). Combined with teaching SEQ ID NO:1 (wherein SEQ ID NO:1 and SEQ ID NO:3 consist of identical nucleobase sequences), Khvorova thus teaches the antisense strand of (mU)#(fG)(mA)(fA)(fU)(fA)(mC)(fU)(mC)(fA)(mA)(fA)(mG)(fU)(mG)(mC)(mA)#ex(mU)#ex(fU) (instant SEQ ID NO:3). Khvorova teaches that the antisense strand comprises a 5’ vinyl phosphonate (claim 44). Khvorova teaches a sense strand comprising both 2’-O-methyl nucleotides (claim 38) and 2’-fluoro-modified nucleotides (paragraphs [0379]-[0380], any of Y or X can be a 2’-fluoro modification or a 2’-O-methyl modification, in any combination, Formula (III)). While Khvorova does not explicitly teach the particular combination of 2’-methoxy and 2’-fluoro modifications as recited in the instant claims, Khvorova encompasses the claimed modified sequences by teaching that any combination of 2’-fluoro and 2’-methoxy modifications of the sense and antisense strands are encompassed, thus rendering obvious the modified sequences of SEQ ID NOs:3-5.
Regarding claim 28, Khvorova teaches a pharmaceutical composition for inhibiting expression of a PRNP gene in an organism, comprising the dsRNA molecule and a pharmaceutically acceptable carrier (claim 68).
Regarding claim 41, Khvorova teaches a branched RNA compound comprising two or more dsRNA molecules (claims 85, 88), wherein each of the dsRNA molecules comprises an antisense strand and a sense strand (claim 91), and wherein the antisense strand comprises a sequence comprising no more than 3 mismatches with SEQ ID NO:3 and comprising 15-25 nucleotides in length (claims 91-93, 95). Instant SEQ ID NO:1 comprises one mismatch relative to the complement of SEQ ID NO:3, and instant SEQ ID NO:2 is substantially identical to (comprising one mismatch relative to) SEQ ID NO:3 (see alignment above) (claim 131, paragraph [030], the sense strand is complementary to the antisense strand).
Regarding claim 47, Khvorova teaches a pharmaceutical composition for inhibiting expression of a PRNP gene in an organism, comprising the branched RNA compound and a pharmaceutically acceptable carrier (claim 173).
Regarding claims 60 and 62, the term “about”, as used in the instant claims, indicates an unlimited margin of error. As such, instant claims 60 and 62 encompass any concentration of branched RNA comprised in the pharmaceutical composition. Khvorova teaches a pharmaceutical composition for inhibiting expression of a PRNP gene in an organism, comprising the branched RNA compound (of unspecified concentration, thus any concentration) and a pharmaceutically acceptable carrier (claim 173). Likewise, instant claims 60 and 62 encompass K(PO4)2, NaCl, Na(PO4)2, and MgPO4 concentrations of 0 mg/mL. Khvorova does not teach pharmaceutical compositions comprising K(PO4)2, NaCl, Na(PO4)2, or MgPO4, thus encompassing certain embodiments of claims 60 and 62.
Regarding claims 64-65, Khvorova teaches a sense strand and an antisense strand comprising both 2’-O-methyl nucleotides and 2’-fluoro-modified nucleotides (paragraphs [0379]-[0380], any of Y or X can be a 2’-fluoro modification or a 2’-O-methyl modification, in any combination, Formula (III)). While Khvorova does not explicitly teach the particular combination of 2’-methoxy and 2’-fluoro modifications as recited in the instant claims, Khvorova encompasses the claimed modified sequences by teaching that any combination of 2’-fluoro and 2’-methoxy modifications of the sense and antisense strands are encompassed. As Khvorova also encompasses instant SEQ ID NOs:1-2 (and instant SEQ ID NO:1 consists of the same nucleobase sequence as instant SEQ ID NO:3, and instant SEQ ID NO:2 consists of the same nucleobase sequence as instant SEQ ID NO:4), the teachings of Khvorova render obvious the particular modified sense and antisense sequences of instant claims 64-65.
Regarding claim 66, Khvorova teaches that the branched RNA compound comprises at least one modified nucleotide or internucleotide linkage of Formula (I):
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Wherein B is a base pairing moiety;
W is selected from the group consisting of O, OCH2, OCH, CH2, and CH;
X is selected from the group consisting of halo, hydroxy, and C1-6 alkoxy;
Y is selected from the group consisting of O-, OH, OR, NH-, NH2, S-, and SH;
Z is selected from the group consisting of O and CH2;
And
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indicates an optional double bond (claim 118).
Regarding claims 67-68, Khvorova teaches that the dsRNA further comprises at least one phosphorothioate internucleotide linkage (claim 29).
Regarding claim 69, Khvorova teaches that the dsRNA molecule comprises a 2’-O-methyl modified nucleotide, a 2’-deoxy-2’-fluoro modified nucleotide, a 2’-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoroamidate, a non-natural base comprising nucleotide, or a mixture thereof (claim 27).
Regarding claim 70, Khvorova teaches that the antisense strand comprises a 5’ vinyl phosphonate (claim 44).
Regarding claim 71, Khvorova teaches that the branched RNA compound comprises a modified internucleotide linkage according to Formula I, wherein W is OCH2, and Z is O (paragraphs [0307], [0309]; claim 118), resulting in instant Formula VI:
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.
Claim(s) 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khvorova (WO2021173984A2) as applied to claim 41 above, and further in view of Aviñó (2011).
The limitations of instant claim 41 are rendered obvious by the teachings of Khvorova, as discussed above.
Regarding claim 46, Khvorova teaches that the branched RNA compound comprises a linker joining two dsRNA molecules (paragraph [066]).
However, Khvorova does not teach that branched RNA molecules comprise linkers between the 3’ end of a first sense strand and the 3’ end of a second sense strand.
Aviñó teaches that branched RNA compounds comprise linkers linking the 3’ ends of sense strands to one another.
Regarding claim 46, Aviñó teaches that branched RNA molecules can by synthesized by linking the 3’ terminus of a first RNA strand to the 3’ terminus of a second RNA strand, using a linker (Fig. 2), and that the linker is attached to the 3’ end of RNA sense strands (page 4, “we introduced the branching modification at the protruding 3’-end of the sense strand”).
Khvorova does not teach which strands are linked in the branched RNA compound, nor which termini are linked. The teachings of Aviñó would render obvious to an artisan at the time of filing at least one specific structure of linkage which could be used to link the dsRNAs of Khvorova to synthesize the branched RNA compound of Khvorova, thus rendering obvious the limitations of instant claim 46.
Claim(s) 30 and 55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khvorova (WO2021173984A2) as applied to claims 1 and 41 above, and further in view of Hassler (US20240287526A1, effective filing date 06/02/2021).
The limitations of instant claims 1 and 41 are rendered obvious by the teachings of Khvorova, as discussed above.
Regarding claims 30 and 55, Khvorova teaches pharmaceutical compositions comprising a dsRNA or branched RNA (claims 68 and 173).
However, Khvorova does not teach that the pharmaceutical composition comprises the dsRNA or branched RNA and a divalent cation, wherein the divalent cation and RNA are present at a molar ratio of 25:1.
Hassler teaches that pharmaceutical preparations of dsRNA may comprise a dsRNA and a divalent cation at a molar ratio of 1:10-1:100 (paragraphs [0002], [0087]; claims 19-22, the RNA may be branched or not branched).
It would have been obvious to a person of ordinary skill in the art at the time of filing that the pharmaceutical compositions comprising the dsRNA or branched RNA of Khvorova would necessarily comprise additional components to facilitate delivery of the dsRNA or branched RNA to cells, tissues, or subjects, and that these additional components could be selected from those used previously in the art for similar or equivalent purposes. Hassler teaches that a therapeutic composition comprising a dsRNA also comprises a divalent cation, with a molar ratio of dsRNA to divalent cation of 1:10 to 1:100, encompassing a ratio of 1:25, as required by instant claims 30 and 55. It thus would have been obvious to an artisan that the composition of Hassler, comprising a dsRNA and divalent cation at a molar ratio in the range of 1:10 to 1:100, could be used as a pharmaceutical composition as required by Khvorova.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 12258566 B2:
Claims 1, 3, 13-17, 20-24, 26-28, 41, 47, 60, 62, 64-71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23, 29, 32, 35, 43, 45-50 of U.S. Patent No. 12258566 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims recite dsRNA molecules and branched RNA molecules comprising paired sense and antisense strands, wherein the antisense strand comprises a sequence “substantially complementary to” (or complementary to at least 10 contiguous nucleotides of) SEQ ID NO:176 (claims 1-2, 8) (SEQ ID NO:176 comprises 15 consecutive nucleotides identical to the sense strand of instant SEQ ID NO:2, and 15 consecutive nucleotides complementary to instant SEQ ID NO:1, encompassing instant SEQ ID NOs:1-2). The issued claims recite the same internucleotide modifications, 5’-terminal modifications, and nucleotide modifications required by the instant claims. Furthermore, the issued claims recite that the sense and antisense strands comprise 2’-fluoro and 2’-methoxy modifications in any combination (claims 37-38, wherein col. 2 lines 63-65 define a modified nucleotide as comprising a 2’-O methyl or 2’-fluoro modification), that they comprise phosphorothioate linkages at the two 3’- and 5’-terminal linkages (claims 4, 15), rendering obvious the modified sequences of instant claims 26-27 and 64-65.
Claim(s) 46 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23, 29, 32, 35, 43, 45-50 of U.S. Patent No. 12258566 B2, as applied to claim 41 above, and further in view of Aviñó (2011).
The teachings of the issued claims are discussed above and render obvious claim 41.
Regarding claim 46, the issued claims recite that the branched RNA compound comprises a linker joining two dsRNA molecules (claim 9).
However, the issued claims do not recite that branched RNA molecules comprise linkers between the 3’ end of a first sense strand and the 3’ end of a second sense strand.
Aviñó teaches that branched RNA compounds comprise linkers linking the 3’ ends of sense strands to one another.
Regarding claim 46, Aviñó teaches that branched RNA molecules can by synthesized by linking the 3’ terminus of a first RNA strand to the 3’ terminus of a second RNA strand, using a linker (Fig. 2), and that the linker is attached to the 3’ end of RNA sense strands (page 4, “we introduced the branching modification at the protruding 3’-end of the sense strand”).
The issued claims do not recite which strands are linked in the branched RNA compound, nor which termini are linked. The teachings of Aviñó would render obvious to an artisan at the time of filing at least one specific structure of linkage which could be used to link the dsRNAs of the issued claims to synthesize the branched RNA compound of the issued claims, thus rendering obvious the limitations of instant claim 46.
Claim(s) 30 and 55 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23, 29, 32, 35, 43, 45-50 of U.S. Patent No. 12258566 B2, as applied to claims 1 and 41 above, and further in view of Hassler (US20240287526A1).
The teachings of the issued claims are discussed above and render obvious the limitations of instant claims 1 and 41.
Regarding claims 30 and 55, the issued claims recite pharmaceutical compositions comprising a dsRNA or branched RNA (claims 7 and 12).
However, the issued claims do not recite that the pharmaceutical composition comprises the dsRNA or branched RNA and a divalent cation, wherein the divalent cation and RNA are present at a molar ratio of 25:1.
Hassler teaches that pharmaceutical preparations of dsRNA may comprise a dsRNA and a divalent cation at a molar ratio of 1:10-1:100 (paragraphs [0002], [0087]; claims 19-22, the RNA may be branched or not branched).
It would have been obvious to a person of ordinary skill in the art at the time of filing that the pharmaceutical compositions comprising the dsRNA or branched RNA of the issued claims would necessarily comprise additional components to facilitate delivery of the dsRNA or branched RNA to cells, tissues, or subjects, and that these additional components could be selected from those used previously in the art for similar or equivalent purposes. Hassler teaches that a therapeutic composition comprising a dsRNA also comprises a divalent cation, with a molar ratio of dsRNA to divalent cation of 1:10 to 1:100, encompassing a ratio of 1:25, as required by instant claims 30 and 55. It thus would have been obvious to an artisan that the composition of Hassler, comprising a dsRNA and divalent cation at a molar ratio in the range of 1:10 to 1:100, could be used as a pharmaceutical composition as required by the issued claims.
Conclusion
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636